Washington manual of allergy, asthma, and immunology 2nd ed subspeciality consult

THE WASHINGTON MANUAL ™Allergy, Asthma, and Immunology Subspecialty Consult Second Edition Editors Shirley Joo, MD Assistant Professor of Medicine Division of Allergy and Immunology Depa

THE WASHINGTON MANUAL ™

Allergy, Asthma, and Immunology

Subspecialty Consult

Second Edition

Editors

Shirley Joo, MD

Assistant Professor of Medicine

Division of Allergy and Immunology

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

Andrew L Kau, MD, PhD

Instructor in Medicine

Division of Allergy and Immunology

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

Series Editors

Thomas M De Fer, MD

Associate Professor of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

Katherine E Henderson, MD

Assistant Professor of Clinical Medicine

Department of Medicine

Division of Medical Education

Washington University School of Medicine

Barnes-Jewish Hospital

St Louis, Missouri

Senior Acquisitions Editor: Sonya Seigafuse

Senior Product Manager: Kerry Barrett

Vendor Manager: Bridgett Dougherty

Senior Marketing Manager: Kimberly Schonberger

Editorial Coordinator: Katie Sharp

Senior Manufacturing Manager: Ben Rivera

Design Coordinator: Holly McLaughlin

Production Service: Aptara, Inc.

© 2013 by Department of Medicine, Washington University School of Medicine

© 2003 by Department of Medicine, Washington University School of Medicine

Printed in China

All rights reserved This book is protected by copyright No part of this book may be reproduced in any form by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews Materials appearing in this book prepared by individuals as part of their official duties as U.S government employees are not covered by the above-mentioned copyright.

Library of Congress Cataloging-in-Publication Data

The Washington manual™ allergy, asthma, and immunology subspecialty

consult – 2nd ed / edited by Shirley Joo and Andrew L Kau.

p.; cm – (Washington manual subspecialty consult series)

Allergy, asthma, and immunology subspecialty consult

Includes bibliographical references and index.

ISBN 978-1-4511-1367-9 (alk paper) – ISBN 1-4511-1367-6 (alk paper)

I Joo, Shirley II Kau, Andrew L III Washington University (Saint

Louis, Mo.) Dept of Medicine IV Title: Allergy, asthma, and immunology subspecialty consult V Series: Washington manual subspecialty consult series.

[DNLM: 1 Hypersensitivity–diagnosis–Handbooks 2 Hypersensitivity–therapy–Handbooks WD 300]

616.97′5–dc23

2012011793

The Washington Manual™ is an intent-to-use mark belonging to Washington University in St Louis to which international legal protection applies The mark is used in this publication by LWW under license from Washington University.

Care has been taken to confirm the accuracy of the information presented and to describe generally

accepted practices However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication Application of the information in a particular situation remains the professional responsibility of the practitioner.

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10 9 8 7 6 5 4 3 2 1

Assistant Professor of Clinical Medicine

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

Ashley Emmert, MD

Fellow in Allergy Immunology

Division of Allergy and Immunology

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

Olajumoke O Fadugba, MD

Senior Assistant Resident

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

Bob Geng, MD

Senior Assistant Resident

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

Seth M Hollander, MD

Fellow in Allergy Immunology

Division of Allergy and Immunology

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

Eric Karlin, MD

Senior Assistant Resident

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

Andrew L Kau, MD, PhD

Instructor in Medicine

Division of Allergy and Immunology

Department of Internal Medicine

Washington University School of Medicine

Senior Assistant Resident

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

K Lindsey B McMullan, MD

Fellow in Allergy Immunology

Division of Allergy and Immunology

Department of Internal Medicine

Washington University School of Medicine

Division of Allergy and Immunology

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

James A Tarbox, MD

Fellow in Allergy/Immunology

Division of Allergy and Immunology

Department of Internal Medicine

Washington University School of Medicine

Division of Allergy and Immunology

Department of Internal Medicine

Washington University School of Medicine

St Louis, Missouri

Chairman’s Note

t is a pleasure to present the new edition of The Washington Manual ™Subspecialty Consult Series: Allergy, Asthma, and ImmunologySubspecialty Consult This pocket-size book continues to be a primaryreference for medical students, interns, residents, and other practitionerswho need ready access to practical clinical information to diagnose andtreat patients with a wide variety of disorders Medical knowledgecontinues to increase at an astounding rate, which creates a challenge forphysicians to keep up with the biomedical discoveries, genetic andgenomic information, and novel therapeutics that can positively impactpatient outcomes The Washington Manual ™ Subspecialty Consult Seriesaddresses this challenge by concisely and practically providing currentscientific information for clinicians to aid them in the diagnosis,investigation, and treatment of common medical conditions

I want to personally thank the authors, who include house officers,fellows, and attendings at Washington University School of Medicine andBarnes Jewish Hospital Their commitment to patient care and education

is unsurpassed, and their efforts and skill in compiling this manual areevident in the quality of the final product In particular, I would like toacknowledge our editors, Drs Andrew L Kau and Shirley Joo, and theseries editors, Drs Tom De Fer and Katherine Henderson, who haveworked tirelessly to produce another outstanding edition of this manual Iwould also like to thank Dr Melvin Blanchard, Chief of the Division ofMedical Education in the Department at of Medicine at WashingtonUniversity School of Medicine, for his advice and guidance I believe thisedition of the Allergy, Asthma, and Immunology Subspecialty Consult willmeet its desired goal of providing practical knowledge that can be directlyapplied at the bedside and in outpatient settings to improve patient care

Victoria J Fraser, MD

Dr J William Campbell Professor

Interim Chairman of Medicine

Co-Director of the Infectious Disease Division

Washington University School of Medicine

Preface

his is the second edition of the Allergy, Asthma, and ImmunologySubspecialty Consult, which incorporates many significant updates tothe prior edition, reflecting current clinical practices and understanding ofallergic and immunologic diseases Since its inception nearly 70 years ago,the Washington Manual ™ has been written with the goal of conveyingrelevant and up-to-date medical information in a clear and concisemanner Like the first edition, this edition of the Allergy, Asthma, andImmunology Subspecialty Consult was written in the tradition of theWashington Manual ™, with the intent of informing the reader aboutcurrent practice in allergy and immunology

The content of this second edition was written by the residents, fellows,and staff of the Washington University Department of Medicine We havewritten this manual as a reference tool for interested interns, residents,medical students, and primary care physicians Fellows-in-training andother health care professionals will also find it to be a succinct butthorough reference tool

We would like to acknowledge our appreciation for the excellent work ofthe authors of the first edition of the Allergy, Asthma, and ImmunologySubspecialty Consult, especially the editors, Dr Barbara C Jost, Dr.Elizabeth Friedman, Dr Khaled M Abdel-Hamid, Dr Alpa L Jani, and Dr.Tammy L Lin Finally, we would like to thank our excellent mentors,including Dr H James Wedner, Dr Anthony Kulczycki, Dr Philip E.Korenblat, Dr Jeffrey Tillinghast, Dr Rand Dankner, and Dr JacquelineReiss

—A.L.K

—S.J

2 Basic Immunology Underlying Allergic Reactions and Inflammation

Jennifer M Welch and Andrew L Kau

3 Allergic Rhinitis and Sinusitis

12 Ocular Allergic Disease

Gregg J Berdy and Susan S Berdy

13 Anaphylaxis

Sydney Leibel

14 Drug Allergy and Desensitization

A Common Medications Used in Allergy and Immunology

B Lab Values for Selected Tests in Immunology

C Sample Schedule for Perennial Aqueous Immunotherapy

Index

1 Approach to the Allergic Patient

Seth M Hollander

GENERAL PRINCIPLES

Definition

The term allergy is credited to the pediatrician Clemons von Pirquet who

in 1906 used it to describe an “altered biologic reactivity.” This was notonly in reference to immunity against disease but also tohypersensitivity leading to tissue damage.1

The modern definition of allergy is an overreaction or abnormal response

of the immune system to innocuous substances.1

Exacerbating or alleviating factors:

Seasonal variation of symptoms

Prior response to medications

Reactions to specific and nonspecific exposures

not be obvious to the patient.

Typical questions that may help to identify relevant exposures include: Location of home: Rural, urban, suburban

Work exposures

Hobbies, sports, etc

Presence of water damage at home or work place or visible mold

Presence of pets

Age of mattress/bedding

Age of carpeting at home

Family History

Allergic diseases have a strong hereditary link

A parental history of allergic rhinitis increases a 6-year old’s odds ofallergic rhinitis by 1.84 (1.16–2.94).2

A parental history of asthma increases a 6-year old’s odds of asthma by2.72 (1.19–6.18).2

A maternal history of eczema or atopy increases a 6-month old’s risk ofeczema by 1.58 (1.01–2.47) and 1.99 (1.43–2.78), respectively.3

Food Allergy History

While allergies to food are thought to be much more common inchildren, they are also seen in adults in comparable numbers.4

Food allergies are often implicated, (with a prevalence of 3–35%),4

more often than they are proven to be true (actual prevalence rate of 1–10.8% after oral food challenge4 , 5) A thorough history can lead toappropriate testing, which may further help to confirm or excludesuspected foods

Infraorbital folds or Dennie–Morgan lines may be present.

Patients may be observed to rub upward across their nose with the palm

of the hand This is known as the “allergic salute” and may cause a

transverse line across the lower portion of the nose or nasal crease

Head and Neck

Eyes are commonly noted to have conjunctival injection and wateringdue to allergic disease

Common allergic features of the nose include swollen, edematousturbinates that are pale blue in color

Presence of nasal polyps which often appear like clear whitish sacshanging from the underside of a turbinate

Close examination of nasal septum to assess presence of perforations ordeviations

Tympanic membranes may be dull with the presence of effusion behindthem

Flexible rhinoscopy is helpful in looking closer at the turbinate

anatomy and vocal cords to assess for the presence of nasal polyps,sinusitis, or vocal cord dysfunction

Pulmonary

A thorough lung exam is required, including auscultation of all lungfields, to listen for any evidence of wheezing or an increased expiratoryphase

If wheezing cannot be heard during a standard exam, a forced expiratorymaneuver may be helpful

Skin

Urticaria, or hives, is a maculopapular erythematous eruption in the

cutaneous tissues These can range from pinpoint size to multiple inches

in diameter and are typically pruritic and blanch with pressure

Angioedema is edema of the subcutaneous tissue; nonpruritic and

often painful

Dermatographism is the tendency to form a wheal and flair response

when firm pressure is applied to the skin

Atopic dermatitis is associated with allergic disease This presents as

dry, scaly, pruritic patches occurring at typical locations depending onthe age of the patient

Diagnostic Testing

As with all testing, the results must be interpreted with appropriate clinicalcontext as to distinguish between sensitization and symptomatic allergy

Skin Testing

This is the most rapid and specific method to test for allergic sensitivity Two methods are commonly used, and both are discussed in Chapter 8: Epicutaneous testing.

Intradermal testing

In Vitro Tests

In vitro testing (radioallergosorbent test [RAST] and ImmunoCAP) isdesigned to screen for the presence of allergen-specific immunoglobulin

E (IgE) in the patient’s serum

These methods have lower sensitivity and specificity compared toepicutaneous skin testing but are helpful in instances where skin testingcannot be performed

Pulmonary Testing

When a history of breathing difficulties, wheezing, or coughing isreported, pulmonary function tests are often needed to evaluate forasthma

Occasionally a plain chest radiograph is helpful

When standard pulmonary function tests are normal, but there is still ahigh suspicion for asthma, modifications may be needed as follows:

3 Moore MM, Rifas-Shiman SL, Rich-Edwards JW, et al Perinatal predictors

of atopic dermatitis occurring in the first six months of life Pediatrics.2004;113:468–474

4 Rona RR, Keil T, Summers C, et al The prevalence of food allergy: ameta-analysis J Allergy Clin Immunol 2007;120:638–646

5 Lieberman JA, Sicherer SH Diagnosis of food allergy: epicutaneous skintests, in vitro tests, and oral food challenge Curr Allergy Asthma Rep.2011;11:8–64

2 Basic Immunology Underlying Allergic

Reactions and Inflammation

Jennifer M Welch and Andrew L Kau

GENERAL PRINCIPLES

Definitions

The immune system is responsible for protecting us from bacterial, viral,fungal, and helminthic pathogens At the same time, the immunesystem must remain tolerant to self-derived antigens, antigens present

on commensal organisms, proteins in food, and antigens present in theenvironment

Autoimmunity results when there is loss of immunologic tolerance to

“self”-antigens

Allergy is the result of loss of tolerance to environmental or food

antigens (also called allergens)

Immunodeficiency describes the lack of appropriate immune

response to a pathogen that results in recurrent infection

Components of the immune system include the innate and adaptivesystems

Innate Immune System

The innate immune system comprises lymphoid-derived cells (e.g.,neutrophils, macrophages, dendritic cells, eosinophils, etc.), non-lymphoid tissues (e.g., epithelial cells), and proteins capable ofpathogen recognition

Innate immune cells are able to identify pathogens through pattern

recognition receptors (PRR) that distinguish conserved features of

pathogens, termed pathogen-associated molecular patterns

(PAMP)

Adaptive Immune System

Cellular immunity, or cell-mediated immunity, consists of the

response mediated by T cells

Types of CD4+ T cells are classified by the type of cytokines that they

Tregs (or regulatory T cells) are a subset of T cells that mediatetolerance to both self-antigens and exogenous antigens They expressimmunoregulatory cytokines such as transforming growth factor(TGF)-β.

Humoral immunity is mediated by antibodies produced by B cells.

Immunoglobulin G (IgG) is present primarily in the serum and helpsprotect from viral and bacterial pathogens

IgA is produced primarily on mucosal surfaces, protects againstpathogens on the mucosal surface, and helps maintain homeostasiswith colonizing microbes

IgE is thought to protect from parasitic infections and is responsible forallergic reactions

TABLE 2.1 HYPERSENSITIVITY REACTIONS

Classification

Gell–Coombs provides a classification for immune-mediated

hypersensitivity reactions and is divided into four types that are shown in

Table 2-1

Etiology

Allergy develops when B cells are stimulated to produce IgE antibody to

an environmental or food antigen

The hygiene hypothesis was formulated to help explain the increase

of allergic disease in developed countries over the past few decades Itpostulates that reduced exposure to infections in early childhood due toimproved living standards, hygiene, and smaller family size results inless TH1 stimulation and thus an increase in TH2-mediated diseases Children living in rural areas with heavy exposure to animals have alower prevalence of allergy and asthma compared to children living inthe same area without exposure to animals.1

Antigens that mediate allergic reactions (also called allergens)

comprise a wide variety of molecules, including chemicals and proteinscommonly encountered in a person’s environment Examples includedust mite, pollen, and animal dander Some chemicals are able to elicit

an immune response by binding to self-proteins creating a hapten–carrier conjugate This is seen in penicillin allergy

IgE is a 190 kD immunoglobulin found in minute amounts in the serum.

It circulates as a bivalent antibody, and in pathologic conditions, such asparasitic infection or severe atopy, these levels can rise in the serum.IgE is synthesized by B cells that are activated and differentiated intoplasma cells that secrete IgE

Activation of B cells to make IgE requires IL-4 or IL-13 as a helpersignal that is secreted by TH2 helper CD4+ cells

Once secreted, IgE binds to Fc receptors on tissue mast cells tosensitize these cells to allergens

There are two main types of IgE receptors, a high-affinity Fc

receptor called FcεRI and a low-affinity Fc receptor called FcεRII Thehigh-affinity receptor is located on mast cells, basophils, dendriticcells, eosinophils, and Langerhans cells

The high-affinity FcεRI receptor is composed of α-chain that

binds to the Fc portion of IgE, a β-chain and two γ-chains that areinvolved with intracellular signaling Eosinophils do not contain theβ-chain

The presence of IgE increases FcεRI expression on the surface ofmast cells Individuals with higher IgE levels need a smaller triggerfor mast cell activation.

The allergic response is composed of two phases: Immediate and late

phase

The immediate response occurs when antigen binds to mast cell–

associated IgE (which is bound to the surface of the mast cell by itshigh-affinity receptor, Fc εR1) This causes cross-linking of IgE andstimulates mast cell to release its preformed granules This reactioncan appear within 5–10 minutes after the administration of antigenand usually subsides in an hour The wheal-and-flare response seenduring allergy skin testing (see Chapter 8) is an example of animmediate allergic response

The late-phase reaction is mediated by cytokines and lipid

mediators produced by mast cells along with neutrophils, eosinophils,basophils, and TH2 T cells recruited to the site The late-phasereaction occurs 2–4 hours after the immediate response, and theinflammation is maximal by 24 hours before it subsides Late-phaseallergic inflammation can be reduced with corticosteroids but notantihistamines

Mast cells arise from CD34+ bone marrow progenitors and migrate as

immature cells to peripheral tissue where they mature near bloodvessels, nerves, and beneath epithelia Mast cells vary in shape andhave round nuclei with cytoplasmic granules containing acidicproteoglycans that bind to basic dyes

Activated mast cells are a key component to allergic reactions Theysecrete various mediators that are either stored pre-formed ingranules or synthesized upon activation

Pre-formed granules consist of biogenic amines (histamine),

neutral proteases (tryptase, chymase, carboxypeptidase), acidhydrolases, proteoglycans (heparin, chondroitin sulfate), and tumornecrosis factor (TNF)-α These are released within minutes of cross-linking of surface-bound IgE

Histamine acts upon release on the four different histamine

receptors Its actions are short lived, because it is rapidly removedfrom the extracellular space

Through the H1 receptor, histamine causes smooth muscle

contraction (bronchospasm), pruritus, vasodilation, andvasopermeability This creates the wheal- and-flare response onthe skin.

The H2 receptor is responsible for gastric acid secretion andincreased mucus production in the airways

The H3 receptor is found in the nervous system and controls therelease of histamine and other neurotransmitters

The H4 receptor aids in chemotaxis of mast cells

Tryptase is found only in mast cells and is a marker of mast

cell activation Tryptase cleaves fibrinogen and activates

collagenase causing tissue damage Tryptase is found in two forms,α-tryptase and β-tryptase

α-Tryptase is constitutively secreted Levels are elevated in thedisease mastocytosis

β-Tryptase is released upon mast cell degranulation It is stabilized

by heparin Blood level peak 30 minutes after anaphylactic reactionbut may remain above baseline level for 6–12 hours after incitingevent

Synthesized mediators are made by mast cells minutes to hours

after activation and include arachidonic acid metabolites andcytokines

Lipid metabolites are created from arachidonic acid via thecyclooxygenase or lipoxygenase pathways and are mediators inallergic reactions

Prostaglandin D2 (PGD2) is synthesized through thecyclooxygenase pathway PGD2 acts on smooth muscle cells tomediate vasodilatation and bronchoconstriction It also promotesneutrophil chemotaxis

Leukotrienes are created via the lipoxygenase pathways.

Leukotriene C4 (LTC4) is made by mucosal mast cells and isdegraded to LTD4 and LTE4 These are important mediators ofasthmatic bronchoconstriction In addition, they also increasevascular permeability and mucus secretion

Platelet-activating factor (PAF) causes bronchoconstriction,

vascular permeability, relaxes vascular smooth muscle, and canactivate leukocytes PAF has a short half life as it is rapidly

destroyed It received its name as it causes rabbit plateletaggregation.

Mast cell synthesized cytokines that contribute to allergic

inflammation include the following:

IL-3 induces mast cell proliferation

IL-4 and IL-13 promote IgE isotype switching and mucus secretion IL-5 activates and induces eosinophil proliferation

IL-6 promotes B-cell differentiation

TNF-α activates endothelial expression of adhesion molecules thataid in leukocyte recruitment

Mast cells can be stimulated to release their mediators by:

Allergens binding to surface IgE on mast cells causing cross-linking.Cross-linking describes the process of simultaneous engagement ofmultiple IgE Fc receptors necessary for signaling

Antibody binding to IgE or FcεR1 receptor causing cross-linking

Histamine releasing factors that include chemokines such asmacrophage inflammatory protein (MIP)-1, complement factors C3aand C5a, and neuropeptides like substance P

Drugs (morphine, codeine) and IV contrast dye

Physical stimuli such as pressure, heat, cold, and sunlight

Basophils are a blood granulocyte with a similar function and structure

to mast cells

Their name is derived from the ability of their granules to bind to basicdye Basophils can synthesize many of the same mediators as mastcells

Basophils also express FcεR1 receptor and can be activated by antigenbinding to IgE

Basophils make up less than 1% of blood leukocytes They arenormally not present in tissue, but may be recruited to sites ofinflammation

Eosinophils are a blood granulocyte that is commonly involved in

allergic diseases

Eosinophil maturation is promoted by granulocyte macrophage stimulating factor (GM-CSF), IL-3, and IL-5 They are normally seen inperipheral tissue and are recruited to sites of inflammation mainly inthe late-phase reaction

Their granules contain basic proteins that bind to acidic dye

Eosinophils have receptors for IgG, IgA, and IgE Once activated,eosinophils produce major basic protein, eosinophil cationic protein,and eosinophil peroxidase, which are toxic to bacteria, helminths, andnormal tissue They can also release lipid mediators that aid in theallergic response.

REFERENCE

1 von Mutius E Influences in allergy: epidemiology and the environment

J Allergy Clin Immunol 2004;113:373–379

3 Allergic Rhinitis and Sinusitis

AR symptoms are caused by environmental allergens

The prevalence of AR is increasing

Rhinitis includes AR, nonallergic rhinitis (NAR), and nonallergic rhinitiswith eosinophilia syndrome (NARES)

Definition

AR is allergen-driven mucosal inflammation

AR must contain one or more of the following symptoms:1

For rhinitis to be classified as allergic, the patient must have evidence

of immunoglobulin E (IgE) sensitization to an allergen by skin

testing or radioallergosorbent test (RAST)

Other associated symptoms include palatal pruritus, pruritus of the earcanals, ocular pruritus and watering, and some patients have anosmia orreduced sense of smell

Nonallergic rhinitis (NAR) is not mediated by IgE.

There is nasal mucosal inflammation

Symptoms are similar to AR usually without itching

No sensitization to allergens is demonstrated

NARES is NAR with eosinophilia syndrome.

Symptoms are very similar or identical to AR.

There is no IgE sensitization to allergen

Large numbers of eosinophils are present on nasal smear (may be

Seasonal AR: Patients have signs and symptoms of AR occurring in

only one or more seasons, but not year round They are sensitized toseasonal allergens such as trees, grasses, or weeds

Perennial AR: Patients have signs and symptoms of AR throughout

the year, though they may also have seasonal exacerbations if theyare sensitized to seasonal allergens

Allergens typically include dust mites, molds, pet dander, or insects Symptoms must be present >2 hours/day, >9 months out of theyear

Episodic AR: Patients have signs and symptoms of AR to allergens

they are sensitized to, but which are not present regularly in theirenvironment An example would be a patient who has symptomswhen visiting a friend who has a cat, but the patient does not comeinto daily contact with the cat.1

Mixed rhinitis: Patients have a combination of AR and NAR.

Epidemiology

AR affects between 10 and 30% of all adults.1

Mixed rhinitis affects 44–87% of patients with rhinitis.1 , 2

In 2002, the financial burden in the US (direct and indirect costs) wasestimated at $11.58 billion.1

Prevalence ranges from 3 to 19%

80% of AR develops before age 20

Equal male and female distribution among adults

Adults have a higher prevalence of perennial AR and children have ahigher prevalence of seasonal AR

Allergens: Sensitization to aeroallergens may occur even in the first 2

years of life.1

Anatomic causes of rhinitis include septal deviation, foreign bodies,

adenoid hypertrophy, choanal atresia, and tumors

Mast cells degranulate and cause release of pre-formed mediators andnewly synthesized mediators that cause the allergic reaction.2

Preformed mediators include histamine, tryptase, chymase,kininogenase, heparin, and other enzymes

Newly formed mediators include prostaglandins, leukotriene (LT) C4,LTD4, and LTE4

Nasal congestion is typically a late-phase response

Eosinophils release mediators causing tissue damage in the late phaseresponse.1

Priming occurs with prolonged allergen exposure resulting in repeated

late-phase responses even with very small exposures—inflammatorymediators continue to be released and symptom resolution may lagbehind the decrease in pollen.1

NAR causes include hormonal, vasomotor, and medication-induced

Risk Factors

Family history of atopy

Serum IgE >100 IU/mL before age 6

Higher socioeconomic status

Presence of a positive skin prick test.1

First-born children are more likely to have AR

Environmental risk factors include smoke exposure and allergenexposure in infancy

DIAGNOSIS

Occasionally, chronic cough may be the presenting symptom.

Often patients can associate the onset of symptoms to a particulartrigger

Common comorbidities include:1

Asthma

Obstructive sleep apnea

Nasal obstruction from severe nasal septal deviation

Inferior turbinate hypertrophy

Adenoidal hypertrophy

Refractory sinusitis

Allergic conjunctivitis

History

History is the most important step in diagnosis.

Important elements of the history:

Frequency of symptoms

Severity of symptoms (both past and present)

Relationship to past symptoms

Length of time symptoms appear after triggers

Triggers may be multiple.

Assess whether the symptoms occur at home and/or work on vacation

Assessment of home environmental conditions should include:

Water damage or mold

Pets

Carpet

Age of pillow and mattress, type of fillers

What other irritants are nearby (e.g., farms, woods, and vacant lots)? Are heat and air conditioning central?

Use of fireplace or humidifiers

Are symptoms exacerbated by dusting or vacuuming the house?

Medications specifically inquire about:

Does the patient take aspirin, nonsteroidal anti-inflammatory drugs(NSAIDs), oral contraceptives, angiotensin-converting enzyme (ACE)-inhibitors, or β-blockers?

What are current and past medications used to treat AR?

Family history of atopic disease should be determined.

Quality of life should be assessed.

Ask about fatigue, learning and attention problems, and sleepdisturbance

Ask about time missed from work or school

Effect on quality of life is often under-recognized and inadequatelytreated.1

Rhinorrhea should be described as predominately clear Persistent,colored rhinorrhea may indicate sinus disease

Time frame of exacerbations should be established

Are symptoms always worse on awakening?

Are there particular seasons that are worse?

Are symptoms completely gone during portions of the year?

Physical Examination

A thorough examination of the head, eyes, ears, nose, and throat should

be performed

Note if findings are unilateral or bilateral

Common findings in AR include:

Allergic salute is a crease across the bridge of the nose and is a

result of rubbing the nose

Dennie’s lines are infraorbital creases.

Conjunctivitis may be present in those with ocular symptoms.

Allergic shiners are infraorbital hyperpigmentation secondary to

Ears should be evaluated for otitis or Eustachian tube dysfunction

It should be noted whether septal deviation or nasal polyps are

present

Care should be taken to ensure there is no sinusitis (see below)

Heart and lung examination should be performed Note whetherwheezing is heard on lung examination.

The skin should be examined for signs of atopic dermatitis

If septal perforation is present, differential diagnosis includes:

Inappropriate use of nasal medications

Adverse effects of other nasal medications

Intranasal narcotic abuse

Previous surgery

Systemic granulomatous disease

Differential Diagnosis

The differential diagnosis of rhinitis is presented in Table 3-1

TABLE 3.1 DIFFERENTIAL DIAGNOSIS FOR RHINITIS

Vasomotor rhinitis:

This is a type of NAR in which excessive vasomotor activity leads tochronic nasal congestion

The mechanism is not completely known

Etiologies include odors, alcohol, spicy foods, emotions,

temperature change, and bright lights.

Drug-induced rhinitis:

Common offenders include ACE-inhibitors, β-blockers, ASA, NSAIDs,oral contraceptives, phosphodiesterase-5-selective inhibitors, α-

receptor antagonists, and cocaine.

Occurs from prolonged use of intranasal decongestants.

Rebound congestion occurs and later nasal hypertrophy This appears

as beefy, red mucosa

Rhinitis medicamentosa will resolve on discontinuation of the agent

Nasal polyps are outgrowths from the nasal passages.

Polyps typically start at the lateral wall and appear smooth, round,pale, and gelatinous

Growth likely occurs from eosinophil-associated growth factors found

in the eosinophils and immunoglobulins they contain

The possibility of cystic fibrosis should be entertained if nasal polypsare found in children

Anatomic abnormalities should be considered, particularly in

difficult-to-treat rhinitis

If cerebrospinal fluid (CSF) rhinorrhea is suspected, evaluate with

β-transferrin in nasal secretions.1

Diagnostic Testing

Skin testing and RAST testing are used to determine allergen

sensitization These are discussed in detail in Chapter 8

Purposes of serum IgE testing are three-fold: To provide evidence ofallergic basis, to confirm suspected allergens, and to determinesuspected sensitivity for avoidance measures and/or immunotherapy.1

Epicutaneous skin testing is preferred

Testing to local trees, weeds, and grasses is usually performed Testing

is also usually performed to molds and perennial allergens

Laboratories

RAST testing is usually used only if skin testing is unable to be

performed

The average sensitivity of serum-specific IgE assays is only 70–75%.1

Reasons for skin testing might be contraindicated include use ofantihistamines, extensive skin disease, and uncooperative patients whoare not able to sit still for 15–20 minutes

Serum IgE and IgG subclasses are not used as diagnostic tools for AR.

Imaging

If anatomic abnormality or chronic sinusitis is suspected, a CT scan may behelpful

Diagnostic Procedures

Rhinoscopy may be used to:

Assess nasal passage structure

Evaluate for nasal polyps and sinusitis

Evaluate vocal chords

Nasal provocation testing is rarely performed and is used primarily for

research purposes to confirm sensitivity to allergen.1

TREATMENT

When treatment with one class fails despite compliance, substitution ofanother class should be considered

If AR is mild, single-agent therapy or combination therapy may be used

in addition to avoidance measures

For all intranasal preparations, patients should be instructed to spray

medication away from the septum to avoid irritation and perforation.Medications

First Line

Intranasal steroids are the mainstay of therapy

They are considered superior to all other medication choices for ARbecause they help prevent both early and late-phase response

Steroids for intranasal use include beclomethasone, budesonide,flunisolide, fluticasone furoate, fluticasone propionate, mometasone,triamcinolone, and ciclesonide

Typical adult dose is two sprays in each nostril daily

Patients with seasonal AR should start intranasal steroids at least 1week before the onset of pollen season

May be used on an as needed basis but this is not as effective as dailyuse.

Systemic side effects are minimal

Patients should be instructed on their proper use to prevent nasalseptum trauma

Nasal examination in patients on nasal steroids should evaluate forcomplications such as septal ulceration and perforation (rare)

Epistaxis may occur, and if frequent, discontinuation of the nasalsteroid should be considered

Oral antihistamines are also commonly used.3

They reduce symptoms of rhinorrhea, nasal pruritus, sneezing, ocularpruritus, and tearing

They are less effective at reducing nasal congestion

Nonsedating second-generation antihistamines include loratadine,desloratadine, fexofenadine, cetirizine, and levocetirizine

First-generation antihistamines are not generally used for ARsecondary to their sedating properties These includechlorpheniramine, diphenhydramine, doxepin, and hydroxyzine

Nasal antihistamines:

These may be as effective or superior to oral second-generationantihistamines.1

They are generally less effective than intranasal steroids

Examples include azelastine and olopatadine

Second Line

Montelukast is approved for seasonal and perennial AR.

Intranasal cromolyn:1 , 3

Inhibits mast cell degranulation

Onset of action is 4–7 days

Effective for episodic AR

Must be used four times daily for maximal effect

Has a good safety profile

Is not as efficacious as nasal steroids or nasal antihistamines

Intranasal anticholinergics (ipratropium):1 , 3

Reduces rhinorrhea

Not useful for nasal congestion

Side effects include epistaxis and nasal dryness

Use with caution in patients with glaucoma or prostate hypertrophy

Nasal decongestants:

Cause vasoconstriction and improve nasal edema, but no actual effect

on the antigen-provoked nasal response.1

Should not be used as single agent.3

Continuous use should be limited to <5 days otherwise may lead torhinitis medicamentosa.3

Examples are oxymetazoline and phenylephrine

Oral decongestants:

Are occasionally useful in selected patients

Most products generally contain phenylephrine

Chronic use of these agents is not recommended.3

Oral steroids:

Are rarely indicated in AR secondary to systemic side effects.

For severe, intractable nasal symptoms or if nasal polyps are present,

a 5- to 7-day course may be considered

Immunotherapy (see Chapter 21):

Immunotherapy may be used for treatment of perennial and seasonal

rhinitis when a specific allergen has been identified.

Successful approximately 80% of the time

Considered unsuccessful if the patient has no relief from symptomsafter 1 year of maintenance therapy

Current recommendations suggest 3–5 years of therapy

Other Nonpharmacologic Therapies

Environmental modification:

Dust mite avoidance:

Dust mite proof covers for mattresses and pillows are designed tohelp decrease the amount of dust mites and other allergens

Vacuum with a HEPA filter.1

Wash linens in hot water

Indoor humidity should be kept <50% to avoid growth of fungi anddust mites.1

Hard surface flooring is preferable

Avoid contact with pets For cat allergen, the cat may be confined to aHEPA-filtered room.1

Pollen counts are highest on sunny, windy days with lower humidity Close windows and doors during pollen season

Performing outdoor activity in the evening when pollen counts arelower.

Mold exposure should be avoided at home

To eliminate fungi, sources of moisture should be eliminatedinitially

Porous surfaces should be replaced

Eliminate cockroaches (much easier said than done)

Wear a HEPA and pollen-proof face mask (e.g., N95) when allergenscannot be avoided

Nasal saline irrigations may help symptoms of chronic rhinitis.1 , 4

SPECIAL CONSIDERATIONS

Pregnancy

Symptoms of AR increase in one-third of pregnant patients.1

Both first- and second-generation antihistamines may be used Cetirizine

is a pregnancy class B medication

Oral decongestants should be avoided, particularly in the first trimester Other medications that may be used include intranasal steroids(budesonide, beclomethasone, fluticasone propionate, class B),montelukast (class B), and sodium cromolyn (class B)

Immunotherapy may be continued without dose escalation duringpregnancy, but immunotherapy should not be initiated duringpregnancy

Intranasal steroids and ipratropium may be used safely

If antihistamines are used, nonsedating agents should be chosen.2

COMPLICATIONS

Medical complications of improperly or untreated AR includerhinosinusitis, otitis media, and rhinitis medicamentosa.1

Psychological impact can include depression, anxiety, low self-esteem,and shyness.

Septal irritation or perforation may occur as a complication of incorrectnasal steroid use

Patients that should be referred to an otolaryngologist for surgicalmanagement include:1

Nasal obstruction from severe nasal septal deviation (septoplasty ispreferred over submucosal resection and has a high reported successrate)

Inferior turbinate hypertrophy requiring reduction in patients who havefailed medical therapy

TABLE 3.2 WHEN TO REFER TO AN ALLERGIST

Adenoid hypertrophy (adenoidectomy)

Nasal polyps which require removal (polypectomy)

Patients with complications from refractory rhinosinusitis (functionalendoscopic sinus surgery).

MONITORING/FOLLOW-UP

Clinical improvement is a better measure for appropriate environmentalcontrol than the amount of allergen concentration.1

Patients should be assessed 2–4 weeks after initiation of therapy.5

Single-agent therapy with intranasal steroids or combination therapywith intranasal steroids and oral antihistamines is usually a goodstarting point

Oral antihistamines should be tried before leukotriene inhibitors.3

Intranasal antihistamines and leukotrienes are more appropriate forthose with seasonal AR.3

If one medication regimen does not seem to be effective, addition of

an agent or change to a different class may be warranted

SINUSITIS

GENERAL PRINCIPLES

Normal sinus function requires:

All sinus ostia must be patent

Normal mucociliary function

Normal local and systemic immune function.2

Rhinitis and sinusitis often coexist and rhinitis often precedes sinusitis.2 , 6

Definition

Sinusitis is simply defined as inflammation of one or more of the

paranasal sinuses

Classification

Sinusitis is classified as acute, chronic, or recurrent

No consensus standards exist for defining chronic rhinosinusitis (CRS)versus acute rhinosinusitis (ARS)

ARS is generally defined as symptoms for ≤1 month.

Nasal drainage must be purulent.2

Of note, acute sinusitis may last up to 12 weeks per episode.6

CRS consists of inflammation of the nasal passages lasting 12 weeks at

a minimum despite medical management.2

Recurrent sinusitis is characterized by >4 episodes of acute sinusitis

per year.6 Patients with recurrent sinusitis may need evaluation forimmunodeficiency

Epidemiology

Ninety to ninety-eight percent of episodes of sinusitis are preceded by anacute viral upper respiratory infection.1

About 31 million people in the US have rhinosinusitis annually.2

Prevalence is estimated at 10–30% in Europe and 15% in America.6

Viral upper respiratory infections become bacterial rhinosinusitis only in 0.5–2% of the population.2

Chronic sinusitis is associated with AR in 60% of adults.2

Increasing resistance to first-line therapies is well known and includes lactamase production (gram-negative organisms) and alterations inpenicillin-binding proteins (gram-positive organisms)

More than one-third of Haemophilus influenza strains and virtually allMoraxella catarrhalis strains are penicillin resistant

Etiology

ARS is usually infectious, viral, bacterial, or fungal.2

Viruses are the most common cause of acute sinusitis.

The most common bacterial etiologies in acute sinusitis are the

following:

Streptococcus pneumoniae

H influenza

M catarrhalis

Staphylococcus aureus, coagulase-negative Staphylococcus, and

anaerobic bacteria are more common in CRS, but CRS is more often

Acute sinusitis often develops when the sinus ostia are obstructedleading to infection

Conditions that disrupt mucociliary clearance of secretions and

promote ostial obstruction predispose patients to sinusitis including:

Primary ciliary dyskinesia

Viral infections and other causes of inflammation may also result inciliary dysfunction

DIAGNOSIS

Clinical Presentation

The diagnosis of rhinosinusitis is usually entirely clinical and thedifferentiation between viral and bacterial infections can be difficult Multiple studies regarding the utility of symptoms and signs fordiagnosing acute sinusitis have sometimes reached differing conclusions

A few have used the true gold standard (i.e., sinus puncture andculture), but more have used a surrogate standard (e.g., sinus plainfilms and CT) Radiography cannot differentiate viral from bacterialsinusitis

ARS symptoms within the first 7–10 days of illness typically indicate aviral rhinosinusitis.2

Regarding ARS, The American Academy of Allergy, Asthma, andImmunology (AAAAI) states the following (strength of recommendationlevel C):7

Acute bacterial rhinosinusitis may be suspected when an upperrespiratory tract infection last longer than 10–14 days

Bacterial infection is more likely with a history of persistent purulent

rhinorrhea, postnasal drainage, and facial pain.

The prominent symptoms of acute bacterial rhinosinusitis are nasalcongestion, purulent rhinorrhea, facial-dental pain, postnasaldrainage, headache, and cough

Signs of ARS include sinus tenderness, purulent nasal discharge,erythematous mucosa, pharyngeal secretions, and periorbital edema The American Academy of Otolaryngology-Head and Neck Surgeryguideline indicates that ARS may be diagnosed by the presence of one

or both of the following:8

Up to 4 weeks of purulent nasal discharge accompanied by nasalobstruction

Facial pain-pressure-fullness

Acute bacterial (rather than viral) rhinosinusitis is diagnosed when: Symptoms or signs persist ≥10 days after the onset of upperrespiratory symptoms or

Symptoms or signs worsen within 10 days after an initialimprovement

The American College of Physicians’ clinical practice guideline advisesthe clinical diagnosis of acute bacterial rhinosinusitis should be made inthose who:9

Have symptoms lasting ≥7 days and

Have maxillary pain or tenderness in the face or teeth and

Purulent nasal secretions

Two or more of the following symptoms when present are helpful whenmaking the diagnosis of CRS in the setting of documented mucosalinflammation:2

Mucopurulent nasal drainage (anterior and/or posterior)

Nasal obstruction or blockage

Facial pain, pressure, and/or fullness

Decreased sense of smell

TABLE 3.3 DIFFERENTIAL DIAGNOSIS FOR SINUSITIS

Differential Diagnosis

The differential diagnosis for rhinosinusitis is presented in Table 3-3

Allergic fungal sinusitis:

Rare cause of chronic sinusitis

The hallmark feature is the presence of sinus opacification due toaccumulation of “allergic mucin” that is thick, inspissated secretionsheavily laden with eosinophils, Charcot–Leyden crystals, and fungalhyphae

Diagnosis usually requires surgery to establish.2

Infectious fungal sinusitis:

More likely to be seen in immunocompromised patients

Aspergillus fumigatus is the most common cause of fungal sinusitis

Diagnostic Testing

Laboratories

If immunodeficiency is suspected, obtain a complete blood count (CBC)

with differential and quantitative immunoglobulin levels Otherwise bloodtests are of little use

Imaging

Imaging to confirm the diagnosis of acute uncomplicated rhinosinusitis isusually not necessary.2 , 7 9